Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

Adang, Laura A.; Bonkowsky, Joshua L.; Boelens, Jaap Jan; Mallack, Eric; Ahrens-Nicklas, Rebecca; Bernat, John A.; Bley, Annette; Burton, Barbara; Darling, Alejandra; Eichler, Florian; Eklund, Erik; Emrick, Lisa; Escolar, Maria; Fatemi, Ali; Fraser, Jamie L.; Gaviglio, Amy; Keller, Stephanie; Patterson, Marc C.; Orchard, Paul; Orthmann-Murphy, Jennifer; Santoro, Jonathan D.; Schöls, Ludger; Sevin, Caroline; Srivastava, Isha N.; Rajan, Deepa; Rubin, Jennifer P.; Van Haren, Keith; Wasserstein, Melissa; Zerem, Ayelet; Fumagalli, Francesca; Laugwitz, Lucia; Vanderver, Adeline

doi:10.1016/j.jcyt.2024.03.487

Cited by 3 publications

(1 citation statement)

References 77 publications

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“…In 2001, a patient was presumably diagnosed with adult-onset metachromatic leukodystrophy (MLD) and then received an allogeneic bone marrow cell (hematopoietic stem cell) transplantation from her unaffected brother, a standard procedure for MLD treatment 25 . After the traditional bone marrow transplantation (tBMT) for 15 years, the disease progress has been halted 7 .…”

Section: Introductionmentioning

confidence: 99%

Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient

Wu,

Wang,

et al. 2024

Preprint

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Microglia play critical roles in the brain physiology and pathology. CSF1R is primarily expressed in microglia. The mono-allelicCSF1Rmutation causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a lethal neurological disease and no rational cure in clinical trials. There are no animal models mimicking human ALSP. In this study, we first developed mouse models based on human ALSP hotspot mutations. We then utilized microglia replacement by bone marrow transplantation (Mr BMT) to replace theCsf1r-deficient microglia in ALSP mice byCsf1r-normal donor cells. With pathogenic gene correction, Mr BMT efficiently attenuated the pathologies. Previously, an ALSP patient received traditional bone marrow transplantation (tBMT) due to a misdiagnosis of metachromatic leukodystrophy. The disease progress was halted for 15 years with unknown reasons. We demonstrated that tBMT in ALSP is equivalent to or close to Mr BMT, achieving efficient microglia replacement and therefore attenuating the ALSP progress in the mouse model. Next, we applied tBMT to replaceCSF1R-deficient microglia in human patients. Our clinical results show that after microglia replacement, the ALSP course is effectively halted. Together, microglia replacement corrects the pathogenic gene and thus halts the disease progress in the mouse model and human patients. This study strongly demonstrates clinical potentials of microglia replacement in neurological disease treatments.

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Section: Introductionmentioning

confidence: 99%

Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient

Wu,

Wang,

et al. 2024

Preprint

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Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

Adang,

Groeschel,

Grzyb

et al. 2024

Molecular Genetics and Metabolism

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UPLC-MS/MS High-Risk Screening for Sphingolipidoses Using Dried Urine Spots

Martineau,

Maranda,

Auray-Blais

2024

Biomolecules

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Background: Early detection of sphingolipidoses is crucial to prevent irreversible complications and improve patient outcomes. The use of urine samples dried on filter paper (DUS) is a non-invasive strategy that simplifies the collection, storage, and shipping of samples compared to using liquid urine specimens. Objectives: (1) Develop and validate a multiplex ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) methodology using DUS to quantify twenty-one lysosphingolipids normalized to creatinine for eight different sphingolipidoses. (2) Establish normal reference values to evaluate the clinical utility of the methodology. Methods: Samples were eluted from a 5 cm filter paper disk (~1 mL of urine) and extracted on Oasis MCX solid-phase extraction cartridges prior to injection in the UPLC-MS/MS system. Results: Urinary lysosphingolipids were stable on DUS at −80 °C and −30 °C for 117 days, at 21.5 °C and 4 °C for at least 26 days, and at 35 °C for 3 days. Globotriaosylsphingosine, glucosylsphingosine, and their analogs were elevated in patients with Fabry disease and Gaucher disease, respectively, compared to controls (p-value < 0.0001). The analysis of related analog profiles suggests a better overall reliability in detecting patients early, especially for Fabry patients. Conclusions: This approach is feasible and might be useful for the early detection, monitoring, and follow-up of patients with sphingolipidoses.

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Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

Cited by 3 publications

References 77 publications

Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient

Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient

Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

UPLC-MS/MS High-Risk Screening for Sphingolipidoses Using Dried Urine Spots

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